# Inhibition of viral entry by interferon-induced proteins

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $355,959

## Abstract

Interferon-inducible transmembrane proteins (IFITMs) exhibit broad antiviral activity, both in cell culture and in
vivo. IFITM expression has been shown to prevent infection of important human pathogens, including influenza,
Ebola, West Nile and SARS viruses, by blocking viral fusion with target cells. The existence of IFITM-resistant
viruses, such as Murine Leukemia and Lassa viruses, suggests that restriction occurs in a cellular compartment-
specific manner. The mechanism by which fusion of diverse viruses is inhibited by IFITMs and the escape
mechanisms from IFITM restriction are not understood, due in part to difficulties associated with visualization of
their dynamic distribution in living cells. We made and validated functional fluorescently-tagged IFITM proteins
and imaged, for the first time, single virus/IFITM co-trafficking and fusion. Pilot experiments suggest that viruses
that co-traffic with IFITMs are trapped at a hemifusion stage, unable to form a fusion pore, whereas resistant
viruses appear to be transported through endosomes devoid of IFITMs. We also discovered a novel role for
phosphoinositides in viral fusion and the IFITM restriction phenotype. Our working hypothesis is that IFITMs
block virus entry by: (i) trapping viral fusion at a dead-end hemifusion stage through by altering the properties of
cell membranes; and (ii) favoring non-productive fusion with intralumenal vesicles within enlarged multivesicular
compartments. We will test the working hypothesis using a panel of validated IFITM-sensitive and –resistant
pseudoviruses and a powerful combination of virology, cell biology, membranebiophysics and advanced imaging
techniques. Specifically, we will: (1) elucidate whether dynamic colocalization of IFITMs with viruses is a
prerequisite for restriction; (2) determine whether IFITMs inhibit viral fusion by altering the mechanical properties
of cell membranes that disfavor the transition from hemifusion to full fusion and/or through diverting the virus
entry to a non-productive pathway; and (3) delineate the role of phosphoinositides in the IFITM restriction
phenotype. Insights into the mechanism of IFITM-mediated virus restriction will provide important clues on how
cells mount efficient antiviral responses and suggest new strategies for preventing infection.

## Key facts

- **NIH application ID:** 9962288
- **Project number:** 5R01AI135806-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Gregory B Melikian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,959
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962288

## Citation

> US National Institutes of Health, RePORTER application 9962288, Inhibition of viral entry by interferon-induced proteins (5R01AI135806-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962288. Licensed CC0.

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